Dendrimers in Neurodegenerative Diseases
Due to a strong anti-amyloidogenic activity, dendrimers are powerful agents with potential application for treatment of Alzheimer’s, Parkinson’s and prion diseases. Moreover, phosphorus containing dendrimer are used for sterilization of medical instrument
- PDF / 326,693 Bytes
- 13 Pages / 439.36 x 666.15 pts Page_size
- 64 Downloads / 207 Views
Dendrimers in Neurodegenerative Diseases
This chapter deals with applications of dendrimers for treatment of Alzheimer’s (AD) and Parkinson’s diseases (PD), as well as the diseases which involve the prion proteins such as scrapie, bovine spongiform encephalopathy (BSE), Gerstmann– Stra¨ussler–Scheinker’s syndrome (GSS), Creutzfeldt–Jakob’s disease (CJD), and its new variant (nvCJD). These neurodegenerative diseases include at least one stage where the formation of amyloidogenic plaques takes place [39, 43, 49]. The accumulation of peptides or proteins with propensity to ˇ-sheet aggregation leads to viscous gel formation and suppression of cellular trophic functions. The neurodegenerative diseases are accompanied with cell damage caused by accumulation of these toxic and pathological proteins [42]. In AD and PD, the aggregation of Aˇ peptide and ˛-synuclein is related to its organism of origin [43], whereas, in prion diseases, it is believed that the misfolded protein is a causative agent of transmissible encephalopathies and can act in an organism different from that of its origin [1, 22, 49]. Whether the seed propagation is responsible for disease transmission is still not clear [43]. Recently, the interactions between Aˇ and prions have been described and attributed to certain role during the pathogenesis [7, 36].
23.1 Dendrimers as Anti-prion Agents In prion-related neurodegenerative diseases, the cellular prion protein (PrPC ) is converted from soluble ˛-helical rich protein to partially insoluble, ˇ-sheet rich, and resistant protein (scrapie form, PrPSc ) toward proteases [1,22,49]. PrPSc aggregates are accumulated in neuronal tissue as a constant feature of all prion diseases. PrPSc is the sole causative agent of the prion diseases [1, 22, 49]. Natural and synthetic prion proteins were studied by X-ray fiber diffraction [73]. PrPSc is very stable toward many chemical and physical treatments [72]; however, its infectivity is completely suppressed when it is exposed to high concentrations of protein denaturants like guanidinium and thiocyanate ions [50]. Since PrPSc inactivation and dissociation proceed via a solubilization of PrPSc , ˇ J. Sebest´ ık et al., Biomedical Applications of Peptide-, Glyco- and Glycopeptide Dendrimers, and Analogous Dendrimeric Structures, DOI 10.1007/978-3-7091-1206-9 23, © Springer-Verlag Wien 2012
209
210
23 Dendrimers in Neurodegenerative Diseases
its solubilizers can serve as a suitable model for PrPSc inactivation [61]. Peptidic ˇ-sheet breakers suppress PrPSc infectivity by interfering with the transition of PrPC to PrPSc and by (partially) unfolding of PrPSc [64]. Another way of PrPSc inactivation is acidic SDS treatment [47]. Several pharmacological strategies for tackling the prion disease have been described [68]. One of them is using dendrimers. Dendrimers are key players in PrPSc deactivation [65, 66, 70]. For example, the G5-PAMAM dendrimer with 64 surface primary amino groups at 0.1 M completely prevented PrPSc -caused toxicity on ScN2a cells. Moreover, the pre
Data Loading...
